Abstract Recent re-evaluation of the results of the Women's Health Initiative shows that estrogen replacement within 10 years of the menopause reduced the incidence of myocardial infarction by 34%. This did not occur if women were started on HRT more than 10 years after the menopause. Others and we showed that estrogen reduces the incidence of cardiac hypertrophy and rescues the heart from ischemia/reperfusion injury in cell and mouse models. In our studies to date, estrogen (E2) acts through ERss to reduce blood pressure, prevent cardiac hypertrophy and fibrosis, and preserve cardiac function in the setting of angiotensin II (AngII) infusion, as a model for human disease. We propose that E2/ERss blocks Ang II or endothelin-1 (ET-1) induced transition of the cardiac fibroblast to myofibroblast and blocks TGFss activation, connective tissue growth factor (CTGF), and matrix mettalloproteinase production. This occurs by estrogen signaling through AMP kinase, blocking Rho/ROCK activation. The ultimate result is decreased collagen gene transcription, as well as other genes that contribute to fibrosis, and all will be tested in isolated cardiac fibroblast and mouse models As a second focus, we propose the idea that E2/ERss up-regulates the apelin/APJ receptor system to block cardiomyocyte hypertrophy, and we will test this concept in myocytes and the apelin KO mouse to establish importance of this interaction. An important transcription factor that represses hypertrophic genes is KLF15. We propose that AngII and ET-1 inhibit the production and nuclear localization of this anti-hypertrophic factor, but E2/ER (and the ER specific ligand, B-LGND) prevent all this, as a novel mechanism for estrogen action. In part this occurs through E2-induced nuclear localization of HDAC5 that de-acetylates and hence maintains the repressive effect of KLF15 on myocardin, preventing cardiomyocyte hypertrophy. In the final Aim, we propose to test a novel ERss agonist from GTx Inc in a mouse model of hypertension, cardiac hypertrophy and fibrosis, using wild type and ERss knockout female and male mice. The hypothesis is that this ligand will be effective in preventing and treating AngII-induced cardiovascular diseases in WT mice, and in both sexes. These data may justify in the future initial translational trials in post-menopausal women, including veterans.